The importance of the cancer stem cell (CSC) concept remains a matter of debate because of limited data demonstrating clinical relevance. Our work has shown that minimal residual disease (MRD) in multiple myeloma (MM), Hodgkin lymphoma, and myeloid leukemias appears to have a stem cell phenotype. Most importantly, preliminary data suggest that CSC behavior predicts relapse in these diseases. These data, perhaps for the first time, suggest that CSCs are in fact clinically relevant and represent the cells responsible for relapse. Our data also suggest that CSCs are often biologically distinct from the tumor bulk, notably exhibiting different sensitivity to drugs. The rapid responses induced by chemotherapy are likely a consequence of their impressive activity against the bulk differentiated tumor cells. The limited durability of many of these responses is consistent with our data showing that the CSCs are resistant to these agents. We have identified and investigated a variety of therapeutic approaches that appear to target CSCs in vitro and successfully translated many into the clinic. Such potential treatments include monoclonal antibodies targeting putative CSC antigens, epigenetic/differentiation therapy, and targeting stem cell pathways. Preliminary data suggest that combining CSC-targeted therapy with treatment that is effective at eliminating tumor bulk offers a novel approach to improving progression-free survival. Allogeneic blood or marrow transplantation (BMT) may be a particularly powerful setting to test CSC targeting strategies, because it provides effective clinical debulking of hematologic malignancies as well as the fact that many of the strategies may also enhance allogeneic antitumor immunity. Therapeutic advance over the past three decades now allow most hematologic malignancy patients to achieve major clinical responses. Although the responses can clearly decrease side effects and improve quality of life, most patients still eventually relapse and die of their disease. Our studies over the past funding period have shown that haploidentical related BMT is now a safe and effective procedure, allowing essentially all patients in need of BMT to now undergo this procedure. The overall hypothesis of this proposal is that targeting MRD in patients at high-risk for relapse after BMT with CSC-directed therapy will reduce relapse. The overall objective is to explore approaches that target leukemia and lymphoma CSCs and translate promising treatments into clinic in the setting of MRD after BMT. A major objective of this project is to also utilize newly-developed sensitive assays for identifying minimal residual CSCs, as correlative assays for evaluating efficacy of the clinical approaches.